Since the first discovery of uvaricin in 1982.sup.1, more than 220 annonaceous acetogenins have been reported. Considerable attention has been paid to this class of naturally occurring polyketide-derived fatty acids due to their pleiotropic biological activities.sup.2, including their immunosuppressive and anti-neoplastic properties. Acetogenins are optically pure compounds frequently containing 1-3 tetrahydrofuran (THF) rings in the center of a long hydrocarbon chain. The stereochemistry of the THF rings may affect the activity of acetogenins since it has been noticed that different stereoisomers of acetogenins display strikingly different biological activity profiles. However, very little is known about the structure-activity relationships contributing to these differences.
Earlier reports described schemes for total synthesis of mono-THF and bis-THF acetogenins..sup.3 However, very few synthetic strategies yielding the central core THF-unit of mono-THF containing acetogenins are stereoselective and therefore require chromatographic separation of the key intermediates..sup.4 FNT .sup.1 Jolad, S. D.; Hoffinan, J. J.; Schram, K. H.; Tempesta, M. S.; Kriek, G. R.; Bates, R. B.; Cole, J. R. J. Org. Chem. 1982, 47, 3151. FNT .sup.2 Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.; McLaughlin, J. L. Natural Product Reports, 1996, 275 and references cited therein. FNT .sup.3 a) Figadere, B.; Peyrat, J.-F.; Cave, A. J. Org. Chem. 1997, 62, 3248 and references cited therein. b) Hoye, T. R.; Ye, Z. J. Am. Chem. Soc. 1996, 118, 1801. c) Figadere, B. Acc. Chem. Res. 1995, 28, 359 and references cited therein. FNT .sup.4 a) Gesson, J.-P.; Bertrand, P. Tetrahedron Lett. 1992, 33, 5177. b) Harmange, J.-C.; Figadere, B. Cave, A. Tetrahedron Lett. 1992, 33, 5749. c) Makabe, H.; Tanaks, A.; Oritani, T. J. Chem. Soc. Perkin Trans. I, 1994, 1975. d) Wu, Y.-L.; Yao, Z.-J. Tetrahedron Lett. 1994, 35, 157. e) Wu, Y.-L.; Yao, Z.-J. J. Org. Chem. 1995, 60,1170.
An efficient and stereocontrolled approach to synthesize the central core THF-unit of mono-THF containing acetogenins which allows each stereogenic center around the THF ring to be controlled is reported in copending patent application U.S. Ser. No. 09/009,057. We have now discovered a novel stereoselective synthetic method for producing the epoxy THF precursor for the total synthesis for mono-THF and bis-THF containing acetogenins.